19-halo-delta-4-10alpha-androsten-17beta-ol-3-one



United States Patent 3,210,389 19-HAL0-A -l0a-ANDROSTEN-flB-DL-El-ONEAlbert Bowers, Mexico City, Mexico, assignor to Syntex Corporation,Panama, Panama, a corporation of Panama No Drawing. Filed Dec. 20, 1962,Ser. No. 246,015 The portion of the term of the patent subsequent toAugust 20, 1980, has been disclaimed 23 Claims. (Cl. 260-397.4)

The present invention relates to novel cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly, the present invention relates to novel 19-halo-A-l0u-androsten-l7fl-ol-3-one derivatives.

The novel compounds of the present invention are represented by thefollowing formulae:

In the above formulae, R represents hydrogen or a hydrocarbon carboxylicacyl group of less than 12 carbon atoms; R represents hydrogen, loweralkyl, lower alkenyl or lower alkinyl; Z represents hydrogen, methylchlorine or fluorine, all having a or B configurations in formula A; Yrepresents a double bond or a saturated linkage each between C1 and C-2;and X represents bromine, chlorine or fluorine.

The acyl group is derived from hydrocarbon carboXylic acids containingless than 12 carbon atoms, which may be saturated or unsaturated, ofstraight, branched, cyclic or cyclic-aliphatic chain, aromatic and maybe substituted by functional groups such as hydroxy, alkoxy containingup to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro,amino or halogen. Typical ester groups are the acetate, propionate,enanthate, benzoate, trimethylacetatae, t-butylacetate, phenoxyacetate,cyclopentylpropionate, aminoacetatae, and ,B-chloropropionate.

The compounds represented by the above formulae have anabolic-androgenicproperties, and inhibit the production of pituitary gonadotrophichormones and A.C.T.H. In addition, they exhibit anti-estrogenic activityand lower the blood, liver and adrenal cholesterol levels. Furthermore,they are very useful in the control of fertility and psychoticconditions, and stimulate the appetite.

The Hot-alkenyl or alkinyl compounds also exhibit progestationalactivity.

The novel compounds of the present invention are prepared by the processexemplified as follows:

OAc OR l l O: O:

(I) (II) 3,210,389 Patented Oct. 5, 1965 "ice A m. a U 0. O: l

i. in O 0 O: I O (VII) Z a l In the above formulas R R X and Z have thesame meaning as previously set forth; R represents hydrogen, lower alkylor lower alkinyl.

In practicing the process outlined above, the starting 17-acetate of19-hydroxy-wot-testosterone (I) is treated with an a-fluorinated amine,such as 2-chloro-1,1,2-trifluoro-trimethylamine in a non-polar organicsolvent, such as methylene chloride to produce the acetate of 19-fluoro-M-lOu-androsten-17,8-o1-3-one (II: Xzfiuorine).

Alternatively, upon conventional treatment of the starting compound (I)with tosyl chloride in pyridine, there is obtained the corresponding19-tosylate which is treated with an alkali metal halide, such aslithium bromide, chloride or fluoride, or silver fluoride, in a suitablesolvent, such as dimethyl formamide or acetonitrile, thus alfording thecorresponding 19-fluoro, chloro or bromo-M-lOa-androsten -01-3-oneacetate (II: R zacetyll) which upon conventional saponification affordsthe corresponding 17,8- free alcohol (II: R zH).

The A -3-ketones (II) upon reaction with ethyleneglycol, in the presenceof p-toluenesulfonic acid yield the corresponding 3-cycloethylenedioxy-Aa androstene compounds (III: R :H) which upon treatment with chromiumtrioxide in pyridine afford the corresponding 3-cycloethylenedioxy-A-10a-androsten-17-ones.

The latter 17-ketones are treated with a lower alkyl magnesium halide,such as methyl magnesium bromide, in a solvent inert to the reagent,e.g., ether, to produce the corresponding l9-halo-3 cycloethylenedioxy17a lower alkyl-A -10ot-androsten-17p-o1 derivatives (III: R :loweralkyl).

When treating the 3-cycloethylenedioxy-A -10a-androsten-l7-ones with acurrent of a lower alkine-l, such as acetylene, in the presence ofpotassium t-amyloxide, there are obtained the corresponding19-halo-3-cycloethylenedioxy-17a-lower alkinyl A-10wandrosten-17p-ol-derivatives (III: R :lower alkinyl).

The 3-cycloethylenedioxy-A -steroids (III) upon treatment with acidunder conventional conditions, yield the corresponding A -3-ketones(IX).

The 3-cycloethylenedioxy-A -compounds (III), upon treatment with anorganic peracid such as monoperphthalic acid, in a suitable solvent,e.g., chloroform, give the corresponding 3-cycloethylenedioxy 19 halo541,606- oxido derivatives (IV).

Upon reaction of the latter 3cycloethylenedioxy-5a,6aoxido compoundswith methyl magnesium bromide in an inert solvent, such as ether ortetrahydrofuran, followed by conventional working up and treatment ofthe resulting residues with a mineral acid, such as 8% sulfuric acid,and thereafter with thionyl chloride in pyridine at about 10 C. forapproximately 4 minutes, there are obtained the corresponding19-halo-6p-methyl-A 10cc androsten- 17/3-ol-3-one derivatives (V:Zzfl-methyl). These 6;?!- methyl derivatives are converted into thecorresponding 6a-methyl derivatives (V: Zza-methyl) by treatment with analkali metal hydroxide.

When treating the 3-cycloethylenedioxy-5a,6a-oxido compounds (IV) withanhydrous hydrogen chloride in a suitable organic solvent, e.g., ethylacetate or acetic acid, there are produced the corresponding6achloro-19-halo-A -1Oa-andmsten-l7,8-ol-3-one derivatives (V:Zza-chlorine).

Upon reaction of the 3-cycloethylenedioxy5a,6aoxido compounds (IV) withanhydrous hydrogen fluoride, preferably in the presence of borontrifluoride etherate, followed by treatment with hydrogen chloride,there are produced the corresponding 6a-fluoro-19-halo-A-1Oa-androsten-17fl-ol-3-one derivatives (V: zza-fluorine).

The 19-halo-A -1Oa-androsten-l7fl-ol-3-one derivatives (II) are treatedwith ethyl orthoformate in the presence of p-toluenesulfonic acid and inan inert solvent, thus affording the corresponding 19-halo-3-ethoxy-A-1Oct-androstadien-17fl-ol derivatives, which upon reaction withapproximately 1 molar equivalent of an N-chloro amide or imide, such asN-chloro succinimide in the presence of sodium acetate and acetic acidyield the corresponding 6B-chloro-19-halo-A-10oc-androsten-17,6-ol-3-one derivatives (V: Zzfl-chlorine). Theaforesaid 19-halo-3-ethoxy-A -10a-androstadien- 17,8-01 derivatives aretreated with perchloryl fluoride in dimethyl formamide to produce thecorresponding 6 8- fluoro-19-halo-A -IOa-androsten-17p-ol-3-onederivatives (V: Zzfi-fluorine).

The 19-halo-17a-alkinyl-A -IOa-androsten-17fi-ol-3-one compounds of thepresent invention (V: R zalkinyl) are converted into the corresponding19-halo-17a-alkenyl-A 10a-androsten-17fl-0l-3-one derivatives (V: Rzalkenyl), by hydrogenation with approximately 1 molar equivalent ofhydrogen, in pyridine solution in the presence of a suitable catalyst,such as 2% palladium on calcium carbonate at room temperature and undera pressure of about 1 atmosphere.

The 19-halo-A -lOa-androsten-17,6-01-3-one compounds of the presentinvention (V) upon treatment with ethyl orthoformate in an inertsolvent, e.g., dioxane, and in the presence of p-toluenesulfonic acid,furnish the corresponding 19-halo-3-ethoxy-A 10a-androstadienederivatives, which are treated with approximately 1 molar equivalent of2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in the presence of acatalytic amount of acid and in an inert solvent to give thecorresponding 19-halo-A -1Ou-androstadien- 17fl-ol-3-one derivatives(VI).

When treating the l9-halo-A -1Oar-androSten-l75-01-3- one compounds (V)with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone in an inert solvent suchas dioxane, preferably at reflux temperature, for a period of time ofabout 10 hours, there are produced the corresponding 19-halo- A-ltla-androstadien-17fi-ol-3-one compounds.

The aforesaid A -androstadiene compounds (VI) are converted into thecorresponding A -androstatriene derivatives by further treatment with2,3-dichloro-5,6-dicyano-l,4-benzoquinone, under the same conditions asspecified hereinbefore for the production of the A -derivatives (VI).

The compounds of the present invention having a secondary hydroxyl,namely the Not-unsubstituted-l7/3-alcohols are conventionally acylatedin pyridine with an acylating agent, such as an anhydride or an acylchloride derived from hydrocarbon carboxylic acids of the previouslydefined type, to produce the corresponding acylates.

The compounds of the present invention having a tertiary hydroxylpresent in the molecule, i.e., the 17lZ-Sllb8tltl1t6d- 17B-alcohols, areconventionally esterified, in the presence of p-toluenesulfonic acidwith an acylating agent such as acetic anhydride or caproic anhydride,thus affording the corresponding esters.

The following specific examples serve to illustrate, but are notintended to restrict the scope of the present invention:

PREPARATION 1 A mixture of 1 g. of 19-hydroxy-wot-testosterone (F.Sondheimer et al., Tetr. Letters, No. 22, 38 [1960]), 3 g. oftriphenylmethyl chloride and 15 cc. of pyridine was heated on a steambath for 2 hours, then it was cooled to 5 C. and 2 cc. of aceticanhydride were added. The resulting mixture was kept at the sametemperature for 24 hours, then it was poured slowly into ice-water andthe resulting precipitate collected by filtration and dried. The drysolid was mixed thoroughly with 20 cc. of acetic acid and there wereadded 3 cc. of a saturated solution of hydrogen bromide in acetic acid.The resulting mixture was stirred for 3 minutes, then poured into icewater and the formed precipitate collected by filtration, washed withwater, dried and crystallized from acetone-hexane, thus yielding the17-acetate of 19-hydroxy-wot-testosterone.

Example I To a solution of 5 g. of the 17-acetate of19-hydroxymot-testosterone in 25 cc. of methylenechloride, were added 5g. of 2-chloro-l,l,2-trifluoro triethyl amine (Yarovenko et al., Journalof General Chemistry of the U.S.S.R. 2125, 29 (1959)). 15 cc. of thesolvent were evaporated under anhydrous conditions and the resultingmixture was kept overnight at room temperature. The reaction mixture wasevaporated to dryness and the residue was chromatographed on alumina,thus yielding compound No. 1, namely, the acetate of l9-fluoro-A-l0otandrosten-17fi-ol-3-one.

Example II A solution of 3.4 g. of the 17-acetate of 19-hydroxy-IDOL-testosterone in 20 cc. of a mixture chloroform-pyridine 9:1 wascooled to 0 C. and mixed with 1.4 g. of tosyl chloride which was addedin small portions. The reaction mixture was kept for 14 hours at 0 C.and then it was washed with dilute hydrochloric acid, water and sodiumbicarbonate solution and the chloroform was evaporated under vacuum. Theresidue, consisted of the crude 19-tosylate. The crude product was driedin vacuum, dissolved in 20 cc. of acetonitrile and treated dropwise with1.4 g. of silver fluoride dissolved in 3 cc. of water. After a shorttime, silver iodine started to separate leaving the 19-fluoro derivativein solution. The mixture was kept for 24 hours at room temperature andfiltered. Concentration of the filtrate under vacuum gave a crudeproduct which after crystallization from methanol-acetone yielded theacetate of 19-fluoro-A -10a-androsten- 175-ol-3-one identical with thefinal product of the foregoing example.

Example 111 A solution of 5 g. of 17-acetate of19-hydroxy-10atestosterone in 25 cc. of pyridine was cooled to C. Understirring there was added 1.3 g. of tosyl chloride, the mixture was keptfor 16 hours at 0 C., diluted with 100 cc. of chloroform, washed withdilute hydrochloric acid, water, aqueous sodium bicarbonate solution andagain with water, dried over anhydrous sodium sulfate and thenevaporated to dryness under reduced pressure. Thus there was obtainedthe crude 19-tosylate of the starting compound.

A suspension of 10 g. of lithium fluoride in 50 cc. of dimethylformamide was heated to boiling and then a solution of 2 g. of the crudetosylate in 10 cc. of dimethyl formamide was added. The mixture wasrefluxed for hours, cooled and poured into water. The formed precipitatewas filtered off and crystallized to give the acetate of 19-fluoro-AIOa-androsten-17,8-01-3-one, identical with the final products of theabove examples.

Example IV The 17 acetate of 19 hydroxy oz testosterone was treatedfollowing the procedure described in Example III except that lithiumchloride was used instead of lithium fluoride, thus affording theacetate of 19-chloro-A -10aandrosten-17fi-ol-3-one (Cpd. No. 2).

Example V A suspension of 1 g. of the acetate of 19-fiuoro-A-10aandrosten-1713-ol-3-one (Cpd. No. 1) in 60 cc. of methanol wastreated with a solution of 1 g. of potassium carbonate in 6 cc. ofwater; the mixture was boiled under reflux for 1 hour and then cooled inice and diluted with water. The formed precipitate was collected andrecrystallized from acetone-hexane to yield 19 fluoro- A-1Oa-androsten-17fl'ol-3-one (Cpd. No. 3).

The compound No. 2 was treated in accordance with the above procedure,thus affording 19-ChlO1'O-A -100candrosten-17/i-ol-3-one (Cpd. No. 4).

Example VI A mixture of 5 g. of compound No. 3, 150 cc. of anhydrousbenzene, 60 cc. of ethyleneglycol distilled over sodium hydroxide and800 mg. of p-toluenesulfonic acid monohydrate was refluxed for 12 hourswith the use of an adapter for the contiuous removal of the water formedduring the reaction. Aqueous sodium bicarbonate solution was added tothe cooled mixture and the organic phase was separated, washed withwater, dried over anhydrous sodium sulfate and evaporated to dryness.The residue crystallized from acetone-hexane to give3-cycloethylenedioxy-19-fiuoro-A -10a-androsten 17B ol (Cpd. No. 5).

When treating Compound No. 4 by the same procedure, there was obtained3-cycloethylenedioxy-19-chloro- A -10a-androsten-17/3-ol (Cpd. No. 6).

Example VII A solution of 6 g. of Compound No. 5 in 120 cc. of pyridinewas added to a mixture of 6 g. of chromic trioxide in 120 cc. ofpyridine. The reaction mixture was kept at room temperature overnight.It was then diluted With ethyl acetate, filtered through celite and thefiltrate washed well with water, dried and evaporated to dryness.

Crystallization from acetone-hexane afforded3-cycloethylenedioxy-19-fiuoro-A -l0a-androsten17-one.

A solution of 5 g. of the latter ketone in 250 cc. of thiophene-freebenzene was treated with 27.5 cc. of 4 N methylmagnesium bromide inether and the mixture refluxed with the exclusion of moisture for 3hours. The cooled mixture was cautiously treated with excess aqueousammonium chloride solution and the product isolated by ethyl acetateextraction. The extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness.

Recrystallization from methylene chloridehexane afforded3-cycloethylenedioxy-19-fluoro-17a-rnethyl-A -10w androsten-17fl-ol(Cpd. No. 7).

When treating compound No. 6 by the above procedures, there weresuccessively obtained: 3-cycloethylenedioxy-19-chloro-A-10a-androsten-17 one and 3 cycloethylenedioxy-19-chloro-17a-methyl A10a-androsten- 17 3-01 (Cpd. No. 8).

Example VIII A solution of 1 g. of 3-cycloethylenedioxy-19-fluoro- A-1Oa-androsten-17-one, in 30 cc. of anhydrous benzene was added, undernitrogen, to a solution prepared by dissolving 1.4 g. of potassium in 30cc. of t-amyl alcohol. A slow current of purified acetylene was passedthrough the solution for 40 hours, whereupon the solution was dilutedwith water and extracted with benzene. The organic extracts were thenwashed to neutral and dried over anhydrous sodium sulfate. Evaporationof the solvent and chromatography of the residue on g. of alkalinealumina gave in the hexane-benzene (2:3) fractions a product, which uponrecrystallization from acetonehexane afforded 3 cycloethylencdioxyl9-fluoro 17aethinyl-A -10a-androsten17B-ol (Cpd. No. 9).

By the same procedure there was treated 3-cycloethylenedioxy-19-chloro A10a-androsten-17-one, to give 3- cycloethylenedioxy-l9-chlorol7a-ethinyl-A -lOa-androsten-17,B-ol (Cpd. No. 10).

Example IX A solution of 500 mg. of Compound No. 7 in 25 cc. of acetonewas treated with 0.1 cc. of concentrated hydrochloric acid and themixture kept at room temperature overnight. It was then poured intowater, extracted with methylene chloride and the organic extract washedwith water to neutral, dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization from acetonehexane gave19-fluoro-17a-methyl-A -10a androsten-17,B- o1-3-one (Cpd. No. 11).

When treating Compounds Nos. 8, 9 and 10, by the above procedure, therewere obtained successively:

Cpd.

12.19-chloro-17a-methyl-A -l0a-androsten- 17fl-ol-3-one,

13.19-fiuoro-17a-ethinyl-A -1Oa-androsten- 17B-ol-3-one,

14.-19-chloro-17a-ethinyl-A -IOa-androsten- 17fl-ol-3-one.

Example X A solution of 2.5 g. of 3-cycloethylenedioxy-19-fluoro- A-1Oa-androsten-17;3-o1 (Cpd. No. 5) in cc. of chloroform was cooled to 0C. and mixed with 1.1 molar equivalents of monoperphthalic acid in ethersolution. The mixture was kept at room temperature for 20 hours, dilutedwith water, the organic layer was separated, washed with aqueous sodiumbicarbonate solution and then with water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. Crystallization fromacetone-hexane gave 3 cycloethylencdioxy 19-fl11010-5oc,6a-oxido-10a-androsten-Up-ol (Cpd. No. 15).

Cpd.

1 6.3-cycloethylenedioxy-1 9Cl1lO1'O-50c,6oc-OXid0-100candrostan- 175-01.

17.3-cycloethylenedioxy-19-fluoro-17a-methyl-5a,6a-

oxido- 1 Ova-androstan- 1 75-01.

18.3-cycloethylenedioxy-19-chloro-l7oz-methyl-5a,6tx-

oxido-la-androstan-17B-01.

l9.3 -cycloethylenedioxy-1 9-fluoro- 17oz6thlI1yl-5ct,6cl,

oxido- 1 Oa-androstan- 1 713-01.

20.3 -cycloethylenedioxy-19-chloro-17a-ethinyl-5a,6ot-

oxido-a-androstan-175-01.

Example XI To a solution of cc. of 4 N methylmagnesium bromide in etherwas added, with stirring, a solution of 1 g. of3-cycloethylenedioxy-19-fluoro-5a,6a-oxido-10a-androstan-17B-ol (Cpd.No. 15) in cc. of dry tetrahydrofuran and the stirred mixture heatedunder reflux for 30 minutes. The condenser was then replaced by acalcium chloride tube, the ether allowed to boil off and when theinternal temperature reached 54 C., the condenser was readapted and themixture refluxed for an additional 4 hours. 200 cc. of a saturatedsolution of ammonium chloride was added slowly to the cooled mixturewhich was then stirred for 15 minutes before transfer to a separatoryfunnel. It was diluted with ethyl acetate, the organic layer wasseparated, dried and evaporated to dryness, thus affording a solidresidue.

A solution of the above residue in 70 cc. of methanol and 7 cc. of 8%aqueous sulfuric acid was refluxed for minutes. It was then neutralizedwith saturated sodium carbonate solution, concentrated to ca. 20 cc. invacuo and poured into water. The formed precipitate was filtered off,washed thoroughly with water and air dried.

A solution of the dry precipitate in 7 cc. of dry pyridine was cooled to10 C., treated with 0.4 cc. of thionyl chloride and the mixture allowedto stand for 4 minutes at this temperature. Ice-water was added and thecrystalline precipitate was filtered, washed and dried, yieldingl9-fluoro-6fl-methyl-A -10u-androsten-17/3-ol-3-one (Cpd. No. 21).

The Compounds Nos. 16 to 20, inclusive, were treated by the aboveprocedure, thus furnishing respectively: Cpd.

No. 22.19-chloro-6B-methyl-A -10a-androsten-l7fl-ol-3-one.23.l9-fluoro-6,B,17a-dimethyl-A -10a-androsten-17B- ol-3-one.24.l9-chloro-6fi,17a-dimethyl-A -10oc-androsten-17(3- ol-3-one.25.-l9-fluoro-6fi-methyl-17a-ethinyl-A -lOa-androsten- 17,8-ol-3-one.26.19-chloro-6;8-methyl-l7u-ethinyl-A -lOu-androstenl7fl-ol-3-one.

Example XII 1 g. of 19-fluoro-6/3-methyl-A -10ot-androsten-175-01-3- one(Cpd. No. 21) was dissolved in 20 cc. of methanol containing 0.2 g. ofsodium hydroxide and the mixture was kept for one and a half hours atroom temperature, then poured into water and extracted with methylenechloride. Evaporation of the methylene chloride solution andcrystallization of the residue from acetone-hexane yielded19-fiu0ro-6a-methyl-A -10ot-androsten-17,8-ol-3-one (Cpd. No. 27).

Following the same procedure, the Compounds Nos. 22 to 26, inclusive,were converted respectively into: Cpd.

29.-l9-flLlOIO-6oz, 17u-dimethyl-A -1 Oar-androsten-l 75- 01-3 -one.

3 0.-l9-chloro-6a,17a-dimethyl-A -IOa-androsten-17/3- ol-3 -one.

3 l.19-fluoro-6a-methyl-17ot-ethinyl-A -1Oa-androsten- 17fl-ol-3-one.

32.19-ch1oro-6ot-rnetl1yl-17a-ethinyl-A -1Oot-androsten- 17 ,8-o1-3-one.

Example XIII Into a suspension of l g. of 3-cycloethylenedioxy-19-fiuoro-5a,6a-oxido-10a-androstan-17fl-ol (Cpd. No. 15) in 35 cc. ofglacial acetic acid, was passed a slow stream of dry hydrochloric acid;after 10 minutes all the solid material was dissolved. The gas waspassed through the reaction mixture for a total of 5 hours. The solutionwas concentrated to about one-third its initial volume by distillationunder reduced pressure at 35 C., then it was poured into ice-water. Theprecipitate formed was collected, washed with water to neutrality anddried. Recrystallization from methylene chloride afforded6achloro-19-fiuoro-A -10oc androsten 17B ol-3-one (Cpd. No. 33).

The Compounds Nos. 16 to 20, inclusive, were treated by the aboveprocedure, thus yielding correspondingly: Cpd.

No. 34.-6a,19-dichloro-A -lOot-androsten-l7 3-o1-3-one. 35.-6a-chloro-19-fluoro-17u-methyl-A -1Ova-androsten- 17,8-ol-3-one.36-60:,19-dichloro-l7a-methyl-A -10a-androsten-17B- ol-3-one.37.6a-chloro-19-fluoro-17zx-ethinyl-A -1Oa-andrQstenl7B-ol-3-0ne.38.6u,19-dichloro-17a-ethinyl-A -10ot-androsten-17B- o1-3-one.

Example XIV 2.8 cc. of boron trifiuoride etherate was slowly added withstirring to 220 mg. of anhydrous hydrogen fluoride cooled in anacetone-Dry Ice bath.

To a solution of 1 g. of Compound No. 15 in 10 cc. of a mixture of equalparts of benzene and ether was added 1.3 cc. of the fluoroboric acidreagent. The mixture was kept for 3 hours at room temperature, thenwashed four times with water, dried over anhydrous sodium sulfate andthe solvent evaporated under reduced pressure. The residue was dissolvedin 50 cc. of ethyl acetate and there was added 1 cc. of concentratedhydrochloric acid. The resulting mixture was kept at room temperaturefor 5 hours, then it was washed abundantly with water. The organic layerwas separated, dried over anhydrous sodium sulfate and evaporated todryness. Recrystallization from acetone-hexane yielded 6a,l9-difluoro-A-10a-androsten-17fi-ol-3-one (Cpd. No. 39).

The Compounds Nos. 16 to 20, inclusive, were treated by the aboveprocedure, thus affording respectively: Cpd.

No. 40.6x-fluoro-l9-chloro-A -lOa-androsten-17,8-01-3-one. 41 .6zx,19-difluoro- 17a-methyl-A -10ot-androsten-1718- ol-3-one.42.6ot-fluoro-19-chloro-17tx-methyl-A -10a-androsten- 17fi-ol-3-one143.-6ot,19-difiuoro-17ot-ethinyl-A -10ot-androsten-17B- ol-3-one.44.6a-fiuoro-19-chloro-17u-ethinyl-A -10a-androsten- 17vc-Ol-3-OI1C.

Example XV A suspension of l g. of 19-fluoro-A-lOzx-andrOstenl7fl-ol-3-one (Cpd. No. 3) in 7.5 cc. of anhydrousperoxide free dioxane was treated with 1.2 cc. of freshly distilledethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture wasstirred at room temperature for 15 minutes and the resulting solutionlet stand for 30 minutes further. 0.8 cc. of pyridine were added andthen water. The formed precipitate was collected by filtration, waterwashed and air dried. Recrystallization from acetone-hexane afforded3-ethoxy-19-fluor0-A androstadien-17p3-ol (Cpd. No. 45).

The Compounds Nos. 4, 11, 12, 13 and 14 were treated by the sameprocedure, thus furnishing respectively:

Cpd. No. 46.3-etl1oxy-19-chloro-A -lOu-androstadien-17fi-ol.47.--3-ethoxy-l9-fluoro-l7oc-methyl-A -10aandrostadien-17fl-ol.48.3-ethoxy-19-chloro-17a-methyl-A -10aandrostadien-17B-ol.49.-3-6th:OXY-1 -flllOfO-17OL-ethlI1yl-'A 100tandrostadien- 17,8-01.50.--3-ethoxy-19-chloro-17u-ethinyl-A -10aandrstadien-17fl-0l.

Example XVI A mixture of g. of 3-ethoxy-19-fiuoro'A-1Ouandrostadien-17fi-ol (Cpd. No. 45), 2 g. of anhydrous sodium acetateand 100 cc. of acetone, was treated with 32 cc. of water and thesolution was cooled to a temperature between 0 and 5 C. There was thenadded 1.1 molar equivalents of N-chloro-succinimide and 2 cc. of glacialacetic acid and the mixture was stirred between 0 and 5 C. for 30minutes. It was then diluted with water, kept overnight at 0 C. and theprecipitate formed was collected, washed with water, dried under vacuumand recrystallized from acetone thus giving 6B-chloro-19- fluoro-A10aandrosten-17,8-ol-3-one (Cpd. No. 51).

The Compounds Nos. 46 to 50, inclusive, were treated by the aboveprocedure, thus yielding correspondingly:

1 g. of 3-ethoxy-19-fiuoro-A -androstadien-175-01 (Cpd. No. 45) wasdissolved in 25 cc. of dimethylformamide. The solution was cooled to 0C. and a stream of perchloryl fluoride was passed for 5 minutes; thesolution was allowed to come slowly to C.; it was then poured into waterand extracted with ethyl acetate. The extract was washed with saturatedaqueous solution of sodium bicarbonate, then with water to neutrality,dried over anhydrous sodium sulfate, and evaporated to dryness. Bychromatography over washed alumina there was obtained 6B,19-difluoro-A-androsten-17B-ol-3-one (Cpd. No. 57).

Upon treatment of Compounds Nos. 46 to 50, inclusive, by the sameprocedure, there were respectively produced:

Example XVIII A solution of 1 g. of 19-fluoro-17ot-ethinyl-A-10otandrosten-17fi-ol-3-one (Cpd. No. 13) in 40 cc. of pyridine washydrogenated at 25 C. and 570 mm. in the presence of 400 mg. ofpre-hydrogenated 2% palladium calcium carbonate catalyst.

When 1.1 molar equivalents of hydrogen had been absorbed, the reactionwas stopped, the catalyst separated by filtration through celite, washedwith ethyl acetate and the combined solutions evaporated to dryness invacuo, yielding the crude vinyl derivative. This crude product wasdissolved in ethyl acetate, the organic solution washed with dilutehydrochloric acid and water to neutral, dried and evaporated to dryness.Recrystallization from acetone gave 19-fluoro-17a-vinyl-A10a-androsten-17fi-ol-3-one (Cpd. No. 63).

Following exactly the same procedure, there were treated the CompoundsNos. 14, 25, 26, 31, 32, 37, 38, 43, 44, 55, 56, 61 and 62, yieldingrespectively:

Cpd.

64-19 chloro 17a vinyl A 10cc androsten 17B- ol-3-one.

65.19 fluoro 65 methyl 17a vinyl A 10aandrosten-17B-ol-3-one.

66.19 chloro 6B methyl 17a vinyl A 10aandrosten-17,8-ol-3-one.

67.19 fluoro 60c methyl 17o: vinyl A candrosten-175-ol-3-one.

68.-19 chloro 6oz methyl a vinyl A 10ozandrosten-17fi-ol-3-one.

69.--6a chloro 19 fluoro 17oz vinyl A 100candrosten-17B-ol-3-one.

' 70.-6a,l9 dichloro 170a vinyl A 100a androsten- 71.6a,19 ditluoro 17avinyl A 10a androsten- 17/3-ol-3-one.

72.6u fluoro 19 chloro 17cc vinyl A 100candrosten-17/3-ol-3-one.

73.-6,8 chloro 19 fluoro 17cc vinyl A 10aandrosten-17B-ol-3-one.

74.-6,8,19 dichloro 17a vinyl A 10a androsten- 17,8-01-3-one.

75.6B,19 difiuoro 17a vinyl A 101x androsten- 17fl-ol-3-one.

76-65 fluoro 19 chloro 17a vinyl A 100candrosten-17l3-ol-3-one.

Example XIX A suspension of 1 g. of 19-fiuoro-A -Mot-androsten-17,8-ol-3-one (Cpd. No. 3) in 7.5 cc. of anhydrous peroxide-free dioxanewas treated with 1.2 cc. of freshly distilled ethyl orthoformate and 0.8g. of p-toluenesulfonic acid. The mixture was stirred at roomtemperature for 15 minutes and the resulting solution let stand for 30minutes further. 0.8 cc. of pyridine were added and then water. Theformed precipitate was collected by filtration, water washed and airdried. Recrystallization from acetone hexane afforded3-ethoxy-19-fluoro-A -IOa-androstadien-17B-ol, identical with CompoundNo. 45 obtained in Example IX.

A solution of 1 g. of the latter compound in 20 cc. of tertahydrofuranwas cooled to 0 C. and there were added 1.05 molar equivalents of2,3-dichlor o-5,6-dicyano- 1,4-benzoquinone and 100 mg. ofp-toluenesulfonic acid. The resulting mixture was further stirred at 0C. for 30 minutes. The precipitated2,3-dich1oro-5,6-dicyanoh'ydroquinone was filtered 01f and 100 cc. ofmethylene chloride were added to the filtrate.

The organic solution was washed with 5% aqueous sodium hydroxidesolution until the washings were colorless, then with water toneutrality, dried over anhydrous sodium sulfate and evaporated todryness. Crystalliza- 1 1 tion from acetone-hexane gave 19-fluoro-A-1Oa-an drostadien-17fi-ol-3-one (Cpd. No. 77).

The Compounds Nos. 4, 11, 12, 1'3 and 14, were treated following thesame procedure, thus yielding respectively:

Cpd.

78 .1 9-chloro-A 1 Owandrostadien- 17 ,B-ol-3-one.

79.19-fluoro-17a-methyl-A 10a-androstadien-17flol-3-one.

80.19-chloro-17a-methyl-A -10a-androstadien-17flol-3-one.

81.19-fluoro-17a-ethinyl-A -IOa-androstadien-17(3- ol-3-one.

82.19-chloro- 17a-ethinyl-A la-androstadien-175- 0l-3-one.

Example XX The Compounds Nos. 21 to 26, inclusive, were treated inaccordance with the preceding example, thus affording respectively:

Cpd.

83 .19-fluor0-6methyl-A -a-androstadien- 176-01- 3 -one.

84.19-chloro-6-methyl-A -IOa-androstadien-1713-01- 3-one.

85.19-fluoro-6, 17a-dimethyl-A IOa-androstadien- 17,8-01-3-one.

86.19-chloro-6,17u-dimethyl-A -10w-androstadien- 17fl-ol-3-one.

S7.19-fiuoro-6-methyl-17ot-ethinyl-A 10aandrostadien-17,8-ol-3-one.

8 8.-19-chloro-6-methyl- 17a-ethinyl-A 10aandrostadien- 17,8-01-3 -one.

Example XXI Upon treatment of Compounds Nos. 33 to 44, inclusive, by theprocedure of Example XIX, there were respectively produced:

Cpd.

89 .6-chl0rol9-fluor0-A 1 Oa-androstadien- 1 7fi-ol-3 one.

90.6,19-dichloro-A -1(lu-androstadien-l7,8-o1-3-one.

9 1 .6-chloro-19-fluoro-17amethyl-A 10aandrostadien-17fl-ol-3-one.

92.6,19-dichloro-17a-methyl-A -10a-androstadien- 17fi-ol-3-one.

93 .6-chloro- 19-fluoro- 17a-ethinyl-A -1Ouandrostadien- 17,8-01-3 -one.

94.-6,19-dichloro-17u-ethinyl-A -IOa-androstadien- 17fi-ol-3-one.

95.6,19-difluoro-A -1Oa-androstadien-175-ol-3-one.

96.-6-fiuoro- 19-chloro-A 1 Oa-androstadien- 17B- ol3-one.

97.6,19-difluoro-17ot-methyl-A -1Oa-andrOstadien- 17,8-ol-3-one.

98.6-fluorol9-chloro- 17OL-H1thy1-A -1OOL- androstadien- 1 75-01-35-one.

100.6fluoro- 19-chloro-17a-ethinyl-A 100candrostadien- 17 {3-01-3-0ne.

Example XXII The Compounds Nos. 63 and 64 were treated according toExample XIX, thus furnishing respectively: 19- fiuoro-17a-vinyl-A-1Oa-andrQstadien-I7fi-ol-3-0ne (Cpd. No. 101) and 19-chlor0-17a-vinyl-A-10a-androstadien- 17,8-ol-3-one (Cpd. No. 102).

Example XXIII A mixture of 500 mg. of 19-fiuoro-A -10a-androsten-17fi-ol-3-one (Cpd. No. 3), 10 cc. of dioxane and 350 mg.

of 2,3-dichloro 5,6 dicyano 1,4-benzoquinone was refluxed for 10 hours.It was then cooled, the 2,3-dichloro- 5,6-dicyano 1,4 benzohydroquinoneformed during the reaction filtered oil, and the filtrate evaporated todryness. The residue was dissolved in acetone and filtered through 10 g.of alumina. Crystallization from acetone-hexane gave 19-fluoro-A-1Ova-androstadien-17B-0l-3-one (Cpd. No. 103).

The Compounds Nos. 4, 11, 12, 13 and 14, were treated in accordance withthe above procedure, thus furnishing respectively:

Cpd.

104 .19-chloro-A 1 Owandrostadien- 17fi-ol-3-one.

105.-19-fiuoro-17a-methyl-A -10u-androstadien-17,8-

ol-3-one.

106.1 9-chloro-17a-methyl-A -10a-androstadien-17B- o1-3 -one.

107.-19-flu0ro-17a-ethinyl-A -IOa-androstadien-17B- ol-3-one.

108 .1 9-chlor0- 17 a-ethinyl-A 1 Ou-androstadienl 7 pol-3-one.

Example XXIV The Compounds Nos. 21 to 32, inclusive, were treated inaccordance with the preceding example, thus alfording respectively:

Example XXV Upon treatment of Compounds Nos. 33 to 44, inclusive, by theprocedure of Example XXIII, there were respectively produced:

Cpd. N0. 121 .6a-chloro- 19-fiuore-A -1Oa-androstadien-l 7(3- ol-3-one.122-611,19-dich1oro-A -1Oa-androstadien-1713-ol-3-one.123.60Chl010-19-1111010-17oc-I1'16thy1-A -h androstadien-17,8-01-3-one.124-60:,19-dichloro-17a-methyl-A -IOa-androStadien- 17,B-ol-3-oue.125.-6a-Ch1010-19-fiI10IO-170c-6th1nylA 1 0aandrostadien-17,8-ol-3-one.126-6,19-dichloro-17a-ethinyl-A -10a-androstadien- 17/3-ol-3-one. 127.6x,19-difluoro-A -1Oa-androstadien-17,8-01-3-one. 128 .6a-fiuoro-19-chloro-A 1 Oa-androstadienl 76- ol-3-one.

129.60c, 1 9-difluoro- 17a-methy1-A 1 Oa-androstadien- 17/3-0l-3-one.

130.6 a-fluorol 9-chloro- 1 7 a-methyl-A -lozandrostadienl7B-ol-3-one.

l32.6a-flu oro- 1 9-chloro-l 7a-ethinyl-A -1Oaandrostadien-17,3-01-3-one.

Example XXVI The Compounds Nos. 63 and 64 were treated according toExample XXIII, thus furnishing respectively: 19- fluoro-17a-vinyl-A-lOa-androstadien-l7fi-ol-3-one (Cpd. No. 133) and 19-chloro-17a-vinyl-A-lOa-androstadien- 17,6-01-3-one (Cpd. No. 134).

Example XXVII The Compounds Nos. 77 to 88, inclusive, upon treatment bythe procedure of Example XXIII, afforded respectively:

Example XXVIII The Compounds Nos. 101 and 102 of Example XXII weretreated in accordance with Example XXIII, thus yielding respectively:19-fluoro 17cc vinyl A1445 100candrostatrien 17,8 o1 3 one (Cpd. No.147) and 19- chloro-l7rx-vinyl-A -a androstatrien 17/3 ol-3-one (Cpd.No. 148).

Example XXIX The Compounds Nos. 65 to 76, inclusive, were treated inaccordance with Example XIX, thus affording the corresponding o-pregnadiene derivatives.

Example XXX A mixture of l g. of l9-fluoro-6fi-methyl-A-10a-androsten-17fi-ol-3-one (Cpd. No. 21), 4 cc. of pyridine and 2 cc.of propionic anhydride was kept at room temperature overnight, pouredinto ice Water, the formed precipitate was filtered, washed with waterand dried. Crystallization from acetone-hexane gave19-fiuoro-6/3-methyl-A -10e-androsten-17fl-ol-3-one propionate (Cpd. No.149).

Upon esterification of Compounds Nos. 22, 27, 28, 33, 34, 39, 40, 51,52, 57, 58, 77, 78, 83, 89, 95, 103, 109, 121 and 135 by the aboveprocedure, there were respectively obtained:

Cpd.

0.-19-ch1oro-6B-methyl-A l0a-androsten-l7fi-ol-3- one-propionate.

15 l .19-fluoro-6a-methyl-A -10a-androsten-17/i-ol-3 one-propionate.

152.-19-chloro-6a-methyl-A -1(ia-androsten-17t3-0l-3- one propionate.

153 .6a-chloro-19-fiuoro-A -10e-androsten-17fl-ol-3 one-propionate.

154-60:,19-dichloro-A -10a-androsten-l75-ol-3 -one propionate.

15 5 .Gcc, 1 9-difluoro-A 1 0a-androsten- 1713-01-3 -one propionate.

15 6.6 a-fiuoro-1 9-chloro-A 1 Oa-androsten- 1713-01-3 -0ne propionate.

15 7.6fi-ch1oro- 19-fluoro-A l Oa-andrOsten- 17/3-01-3 -0ne propionate.

15 8.6B,19-dichloro-A -10a-androsten-17fi-ol-3 -one propionate.

159-65,19-difluoro-A -1Oa-androsten-17fi-ol-3-one propionate.

160.6fi-fluoro-19-chloro-A -10a-androsten-l7l3-ol-3-one propionate.

161.19-fluoro-A lOa-androstadien-1713-ol-3-one propionate.

162.19-ch1oro-A -10u-androstadien-l7fl-ol-3 -one propionate.

163 .l 9-fluoro-6-methyl-A -l Oa-andrOstadien-I 7,8-01- 3-onepropionate.

164.-6-chloro-19-fiuor0-A -10a-androstadien-17,8-01-3 one propionate.

165.6,19-fiuoro-A -10a-androstadien-17,8-01-3-one propionate.

166.-l9-flu0ro-A -l0ot-androstadien-17fi-ol-3 -one propionate.

167.-19-fluor0-6/3-methyl-A -10a-androstadien-17B- ol-3 -one propionate.

168 .6a-chloro- 1 9-fluoro-A l 0a-androstadien- 1713-01- 3-onepropionate.

169.19-fiuoro-A 1 (Ja-andmstatrien-1713-01-3 -one propionate.

Example X X X I The starting compounds of the preceding example weretreated in accordance with that example, except that propionic anhydridewas substituted by caproic anhydride, undecenoic anhydride andcyclopentyl propionic anhydride, thus affording respectively thecorresponding caproates, undecenoates and cyclopentyl propionates ofsaid starting compounds.

Example XXXII To a solution of 5 g. of l9-fluoro-l7a-methyl-A-1Oaandrosten-17fi-ol-3-one (Cpd. N0. 11) in cc. of anhydrous benzenethere were added 1 g. of p-toluenesulfonic acid and 10 Cc. of caproicanhydride and the mixture was allowed to stand for 24 hours at roomtemperature, poured into ice and water, and the resulting mixturestirred to effect hydrolysis of the excess anhydride. The benzene layerwas separated and washed with 10% sodium carbonate solution and water.Drying, evaporation and crystallization of the residue from ether-hexaneproduced 19- fluoro-17a-methyl-A -1Oa-androsten-17fi-ol-3-one caproate(Cpd. No. 170).

Following exactly the same procedure, there were treated the CompoundsNos. 12, 13, 14, 29, 37, 42, 67, 72, 79, 87, 94, 106, 119, 134, 137, and147, thus furnishing respectively Cpd.

171.-19-chloro-17u-methyl-A -10u-androsten-175-01-3- one caproate.

l72.19-fluoro-l7a-ethinyl-A -10a-androsten-17B-ol-3- one caproate.

173.19-chloro-l7a-ethinyl-A -10a-androsten-17B-ol-3- one caproate.

174.19-fluoro-6a,17a-dimethyl-A -10a-androsten-17B- ol-3-one caproate.

15 l75.-6a-chloro-19-fiuoro-17u-ethinyl-A -lOa-andrOstenl7fi-ol3-onecaproate. 176.6oc-fiuoro-l9chloro-17a-methyl-A -10ot-androsten-17,8-ol-3-one caproate. 177.19-fluoro-6a-methyl-l7a-vinyl-A-lOu-androsten- 17l3-ol-3-one caproate.178.6u-fiuoro-19-chloro-17ot-vinyl-A -10a-androsten- 17,8-ol-3-onecaproate. 179.--l9-fluoro-l7a-methyl-A -10a-androstadien-17fiol-3-onecaproate. 180.19-fiuoro-6-methyl-17a-ethinyl-A-10aandrostadien-l75-ol-3-one caproate. 18 l.6,l9-dichloro-17a-ethinyl-A-lOu-andrOstadienl7,8-ol-3-one caproate. 182.19-chloro-l7a-methyl-A-IOa-androstadienl7fl-ol-3-one caproate. 183 .-l9-fluoro-6a-methyl-17a-ethinyl-A 10ozandrostadien l7fi-ol-3-one caproate.184.l9-chloro-17a-vinyl-A -10a-androstadien-17fiol-3-one caproate. 185.l 9-fluorol 7a-methyl-A l a-androstatrien- 17,8-

ol-3-0ne caproate. 186.l9-chloro-l7a-ethinyl-A -lOa-andrOstatrien-17fi-ol-3-one caproate. l87.19-fluoro-l7a-vinyl-A -a-androstatrien-17(3-ol-3-one caproate.

Example XXXIII The starting compounds of the preceding example weretreated in accordance with that example, except that caproic anhydridewas substituted by acetic anhydride, propionic anhydride and enanthicanhydride, thus furnishing respectively the corresponding acetates,propionates and enanthates of said starting compounds.

I claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is amember of the group consisting of hydrogen, lower alkyl, lower alkenyland lower alkinyl; Z is selected from the group consisting of hydrogen,a-methyl, B-methyl, cit-chlorine, fi-chlorine, oc-flllOIil'lC andfi-fluorine; Y is a member of the group consisting of a double bond anda saturated linkage between C-1 and C-2; and X is selected from thegroup consisting of fluorine and chlorine.

2. 19-fluoro-A -10a-androsten-17,6-ol-3-one.

3. l9-chloro-A -10a-androsten-l75-01-3-0ne.

1 55 l 9-flu0ro-17wvinyl-A -l OOL'EiIld rostenl 76-01-3 -one. 19-chloro-1 7u-vinyl-A l 0a-androsten- 17,8-01-3 -one. l9-chloro-17a-methyl-A-l0u-androsten 17p 01-3- l9-fiuoro-l7a-ethinyl-A-lOa-androsten-17B-ol-3-one. 19-chloro-l7a-ethinyl-A -l0a-androsten 17/301-3- one.

9. l9-i'lu0ro 600,170; dimethyl-A -10a-androsten-17flol-3-one.

10. 6ot-Chl010 l9-fluoro-17u-ethinyl-A -IOa-androsten- 1706-01-3-0116.

11. 6u-fluoro 19-chloro-17a-rnethyl-A -lOa-andrOsten 12 19-fluoro cmethyl-17a-vinyl-A -l0u-androsten- 17fi-ol-3-one.

13. 6a-fluoro l9 chloro-17a-vinyl-A -l0a-androstenl7B-ol-3-one.

14. l9-chloro 17cc methyl-A -IOa-andmstadien-17 8- ol-3-one.

15. l9-fluoro 6a methyl-17a,10a-ethinyl-A -androstadien-17B-ol-3-one.

16. 19-chloro 17a vinyl-A -l0a-androstadien-l7fi ol-3-one.

17. A compound of the following formula:

m Y (EH. 1 0 O wherein R is selected from the group consisting ofhydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbonatoms; R is a member of the group consisting of hydrogen lower alkyl,lower alkenyl and lower alkinyl; Z is selected from the group consistingof hydrogen, methyl, chlorine, and fluorine; Y is a member of the groupconsisting of a double bond and a saturated linkage between 0-1 and C2;and X is selected from the group consisting of fluorine and chlorine.

18. 19-fiuoro 171x methyl-A -10a-androstadien-l7flol-3-one.

19. l9-fluoro 6 methyl-l7a-ethinyl-A -IOa-androstadien-l7/3-ol-3-one.

20. 6,19-dichloro 17cc ethinyl-A -10aandrostadienl7fi-ol-3-one.

21. 19-fluoro-17a-methyl-A -1Ozx-andostatrien-17fl-ol- 3-one.

22. 19-chloro 17oz ethinyl h -lOa-andostatrien- 17fi3-ol-3-one.

23. 19-fluoro 17a vinyl A -lOu-andostatrien-1713- ol-3-one.

No references cited.

LEWIS GOTTS, Primary Examiner.

1. A COMPOUND OF THE FOLLOWING FORMULA: